New antiretroviral drugs in clinical use
http://www.100md.com
《美国医学杂志》
Division of Infectious Diseases, Children's Hospital of Michigan, Carman and Ann Adams, Department of Pediatrics, Wayne State University, School of Medicine, USA
Abstract
The advent of combination antiretroviral therapy for the treatment of human immunodeficiency virus (HIV) infection has dramatically changed the prognosis and quality of life of HIV-infected adults and children. To date, there are 21 antiretroviral agents available with only 11 agents being approved for the use in young children less than 6 years of age. The currently available antiretroviral agents belong to four different classes; nucleoside/nucleotide reverse transcriptase inhibitors (NRTI, NtRTI), non-nucleoside reverse transcriptase inhibitors (NNRTI), protease inhibitors (PI), and a new class of fusion inhibitors (FI). It is recommended that the treatment regimen should be a combination of at least 3 drugs from different drug classes as this has been shown to slow disease progression, improve survival, and result in better virologic and immunologic responses. Treatment with antiretroviral agents is frequently complicated by the issues of adherence, tolerability, long term toxicity and drug resistance. Many efforts have been made to develop new antiretroviral agents with greater potency, higher tolerability profiles and better convenience. Some new agents are also effective against drug-resistant strains of HIV. Since 2001, there were 7 new antiretroviral agents and 2 fixed-dose multidrug formulations being approved for the treatment of HIV infection, most are approved only for use in adults. In this article, we will review new antiretroviral agents including emtricitabine, tenofovir disoproxil fumarate, atazanavir, fosamprenavir, tipranavir and enfuvirtide. Pediatric information on these drugs will be provided when available.
Keywords: Antiretroviral drugs; HIV; Children
Emtricitabine (FTC; Emtriva)
Emtricitabine is an NRTI that is structurally similar to lamivudine (3TC), differing only by the addition of a fluorine.[1] When compared to lamivudine, emtricitabine has advantages in term of its longer half life, higher oral bioavailability and greater in vitro activity against HIV.[2], [3] For the treatment in adults, emtricitabine is a component of a preferred initial combination regimen and can be used in place of lamivudine as part of dual NRTI backbone in combination with PI or NNRTI.[4] In clinical trials in HIV-infected adults, emtricitabine-containing combination regimens including the completely once daily regimens, were effective in achieving and /or maintaining suppression of plasma HIV loads to the undetectable levels in both antiretroviral therapy (ART)-naοve[5], [6] and ART-experienced patients switching from a stable combination regimen.[7], [8] When comparing emtricitabine once-daily with stavudine (dAT) twice-daily each in combination with once-daily didanosine and efavirenz in ART-naοve patients, the proportions of patients achieved and maintained HIV RNA <400 copies/ml through week 48 were 81% in FTC group and 68% in d4T group.[5] In ART-experienced patients on lamivudine-containing regimen with HIV RNA <400 copies/ml, 77% of those who were switched from lamivudine to emtricitabine achieved HIV RNA <400 copies/ml at week 48 compare to 82% of those who continued the same regimen.[7] The effectiveness of emtricitabine as a part of combination regimens remains evidenced after 3 - 4 years of treatment.[7] Emtricitabine is also active against hepatitis B virus (HBV)[9] but it has not been approved by Food and Drug Administration (FDA) for use in this indication yet.[10] In children, it is only approved for use in adolescents older than 18 yrs of age.[11] Clinical trials are underway in children using the investigational dose of 6 mg per kg of body weight once daily.[12]
Due to its unique pharmacokinetic characteristics, emtricitabine can be given once daily[13] and without regard to food.[10] Potential drug interaction is minimal because it neither inhibits nor is metabolized by the cytochrome P450 enzyme system.[10] Emtricitabine is excreted by kidney hence dose adjustment is required in patients with renal insufficiency.[10] Tolerability profiles of emtricitabine are similar to those of lamivudine with only minimal toxicities. Common but mild side effects include headache, insomnia, diarrhea, nausea, vomiting and rash.[5], [7] Skin discoloration and hyperpigmentation of palms and soles has been observed in patients using this medication especially in non-Caucasian population.[10] Lactic acidosis, severe hepatomegaly and steatosis occur rarely but can be fatal.[10] Due to its antiviral activity against HBV, there have been cases of HBV exacerbation after discontinuation of emtricitabine[3] therefore screening for HBV/HIV co-infection is recommended before starting treatment with emtricitabine.[4] Liver functions should also be monitored closely for several months after its discontinuation.[4] Resistant profiles of emtricitabine are similar to those of lamivudine and co-administration of the two medications is not recommended.[4] Currently there is a co-formulated product of emtricitabine and tenofovir disoproxil fumarate[14], a new nucleotide analogue reverse transcriptase inhibitor (NtRTI), that can be given once daily in HIV-infected adult patients. The use of this co-formulated product in children is still under study.
Tenofovir Disoproxil Fumarate (Tenofovir DF, TDF; Viread)
Tenofovir disoproxil fumarate is an ester prodrug of tenofovir, an NtRTI.[15] It has been approved for use in combination with other antiretroviral agents for the treatment of HIV infection in adult since October 2001. In pediatric population, it was approved for use only for adolescents older than 18 years of age and is currently under study in children. In in vitro studies, TDF demonstrated a good inhibitory activity against HIV[16] as well as a synergistic/additive effect when combined with other antiretroviral agents.[17] According to the treatment guidelines for HIV-infected adults, TDF is a part of a preferred initial regimen for ART-naοve patients. In a clinical study among ART-naοve adult patients, TDF-containing regimen and the stavudine-containing regimen when each was combined with lamivudine and efavirenz demonstrated virologic suppression with HIV RNA < 400 copies/ml at week 48 in 80% and 84% in TDF group and d4T group, respectively.[18] In ART-experienced adult patients, the data from clinical trials shows that TDF in combination with other antiretroviral agents produced significantly higher viral load reduction than placebo with 40% cases achieved HIV RNA < 400 copies/ml at week 24 in tenofovir group versus 11% in placebo group.[19] In the placebo crossover phase of the study, the proportions of cases with HIV RNA < 400 copies/ml were 28% in TDF group and 30% in those who were switched from placebo to TDF.[19] Because of its once daily dosing, TDF can be used to simplify the treatment regimen among virologically stable patients on a combination antiretroviral therapy.[20] The effectiveness of TDF as a salvage regimen in the case of virologic failure as well as an alternative agent in the case of drug toxicity has also been demonstrated in ART-experienced adult patients.[15] However, suboptimal response and /or early treatment failure have been demonstrated among treatment-naοve patients who received TDF in combination with 3TC and didanosine or 3TC and abacavir.[15]
Due to its long half life of 17 hours, TDF is allowed to be used as a convenient once-daily dosing.[27] Twenty five percent of the drug is absorbed in fasting state and up to 39% is absorbed when given with high fat meal.[21] TDF can be given without regard to food but it is recommended to be taken with high fat meal to enhance its absorption. TDF is eliminated unchanged by kidneys and dose adjustment is required when use in patients with renal insufficiency.[21] Common side effects are that of gastrointestinal disturbances such as nausea, diarrhea, vomiting and flatulence.[21] Severe hepatomegaly with steatosis is the rare but fatal reaction.[22] Although there has been no TDF-associated renal toxicity among adult patients who received TDF up to one year in clinical studies, cases of nephrotoxicity secondary to TDF have been reported in adults.[23],[24] TDF appears less likely to cause mitochondrial toxicity when compared to other NRTIs, however lactic acidosis has been reported with the use of the agent.[24] Similar to 3TC and FTC, TDF has an antiviral activity against HBV[25], therefore exacerbation of HBV after discontinuation of TDF is possible and patients should be screened for HBV prior to initiation of TDF. TDF substantially increases plasma didanosine levels, thus the dosage of didanosine should be decreased to avoid potential toxicity from didanosine. Because TDF lowers plasma atazanavir levels by 25%, a low-dose ritronavir for pharmacokinetic enhancement should always be used in a treatment regimen that contains atazanavir and TDF. In general, resistance to TDF develops slowly and reduced responses to TDF are associated with the L210W, M41L or K65R mutations.
The data is insufficient to make recommendations for the use of TDF in children. With the advantages of convenient once daily dosing without regard to food, less mitochondrial toxicity, fewer drug interaction and slower rate for resistance, TDF is among one of antiretroviral agents with great utility. One of the concerns for use of TDF in children is its potential bone toxicity. There were some evidences of osteomalacia among juvenile animals exposed to high dose TDF.[26] Clinical trials in children are underway.
Atazanavir (ATV; Reyataz)
Atazanavir ( ATV ) is an azapeptide HIV-1 protease inhibitor that targets the protease enzyme, ultimately preventing formation of mature virions.[27] In in-vitro studies, ATV had demonstrated antiviral activity against HIV 2- to 20-fold more potent than other available PIs.[28] ATV is a part of an alternative PI-based combination regimen for the treatment of ART-naοve patients according to the treatment guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. In a clinical trial among antiretroviral naοve adult, the efficacy of ATV was comparable to that of nelfinavir (NFV) with 67% in ATV group and 59% in nelfinavir group achieved HIV RNA of less than 400 copies/ml at week 48, and to that of efavirenz with 67% in ATV group and 62% in efavirenz group achieved HIV RNA of less than 400 copies/ml at week 48 when each was combined with two NRTIs.[29], [30] In ART-experienced patients, the effectiveness of ATV was in the lesser extent compared to lopinavir-ritronavir with the proportions of cases achiving HIV RNA < 400 copies/ml were 49% in ATV group and 69% in LPV group when each drug was combined with 2 NRTIs.[31] In a study in ART-experienced patients who had failed at least 2 regimens, atazanavir-ritonavir and lopinavir-ritonavir each in combination with TDF and 1 NRTI demonstrated a comparable antiretroviral activity with 55% and 57% cases achieved HIV RNA < 400 copies/ml at week 48 in ATV group and LPV group respectively, and both regimens were superior to atazanavir-saquinavir-containing regimen.[32] The concern for use of ATV in ART-experienced patients is the resistance issue. In one study in patients who have previously taken PI, 40% had a reduced susceptibility to ATV.[33] A low dose ritonavir to enhance the pharmacokinetics of ATV should be administered in PI-experienced patients starting on an ATV-containing regimen.
Administration of ATV with a light meal increases its absorption.[27] Antacid, H 2 -blocker or proton pump inhibitor interfere with drug absorption.[24],[34] When used with didanosine, ATV should be taken at least 2 hours before or 1 hour after didanosine to avoid the interference.[27] ATV can be given once daily due to its half-life of 7 hours.[27] It is metabolized mainly by cytochrome P-450 pathway.[27] It is both an inhibitor and a substrate of the enzyme, therefore major drug-drug interaction is expected.[27] Dose adjustment should also be made when used in patients with hepatic insufficiency.[27] One of the advantages of ATV is the lower pill burden with only two pills per day; this may result in better adherence to treatment. Adverse reactions from ATV are generally comparable to those described in protease inhibitors.[35] Common side effects include jaundice, headache, rash and nausea.[34] Hyperbillirubinemia with or without jaundice has been reported during clinical trials of ATV in 35%-49% of patients.[34] The elevations of billirubin commonly occur within the first week of treatment; it is dose-related, reversible after drug discontinuation and not associated with elevation of transaminase enzymes.[34] Prolonged PR interval and asymptomatic first degree AV block are among cardiac effects that have been observed in healthy volunteers receiving ATV.[27] The drug should be used with caution in patients with conduction defect or patients receiving concomitant medications that have the same cardiac side effects.[27] Rare but potential life threatening side effect including Steven Johnson syndrome and severe hepatotoxicity may occur.[33] Hyperglycemia and exacerbation of diabetes mellitus may occur with the use of ATV.[27] Regarding the incidence of lipodystrophy which is one of the major concerns associated with the use of PI, ATV does not disrupt lipids to the same extent as other PIs.[30], [35], [36] In one study, ATV had the same lipid effects as EFV.[30] When ART-experienced patients with severe hyperlipidemia change their treatment regimen to ATV, a sustained improvement in lipid profiles was observed while virologic control was still maintained.[37], [38]
For the use of ATV in children, currently there are insufficient data to make any recommendation. ATV is not approved for use in children less than 16 years of age. The drug should not be used in infants less than 3 months-old due to the possibility of kernicterus. In children, larger dose than adults may be needed and dose finding studies are ongoing. The dose of ATV for adolescents older than 16 years of age is 400 mg once daily in ART-naοve patients and 300 mg in combination with 100 mg of ritonavir once daily in ART-experienced patients. When co-administered with efavirenz or TDF, ATV should always be boosted with ritonavir. In summary, the advantages of ATV are the convenience of once daily dosing, less pill burden and its minimal effect on lipid profiles compares to other PIs.
Fosamprenavir (f-APV, FPV; Lexiva)
Fosamprenavir (f-APV) is a prodrug of an HIV protease inhibitor, amprenavir (APV).[39] It has been approved for use in combination with other ARV agents for the treatment of HIV infection in adults since October 2003. After oral administration, f-APV is rapidly hydrolyzed to amprenavir, the active substrate, by enzymes in the gut epitheliums as it is absorbed.[39] The prodrug formulation of f-APV, with improved solubility[40], substantially reduces the number of tablets per dose when compared to the parent molecule APV.[41] From the pharmacokinetic study in healthy adult volunteers, f-APV delivers plasma concentrations equivalent to the recommended therapeutic dose of APV but with less pill burden.[40] Fosamprenavir also demonstrated less gastrointestinal side effects when compared to APV.[41] In two clinical trials in ART-naοve adult patients, f-APV and ritonavir boosted f-APV demonstrated the similar virological and immunological efficacy as nelfinavir when each was combined with abacavir and 3TC.[42], [43] In ART-experienced patients with prior virological failure, 58% of patients who received a ritonavir-boosted f-APV regimen achieved and maintained virologic suppression with HIV RNA of less than 400 copies/ml at week 48 compared to 61% of those who received a ritonavir-boosted lopinavir regimen.[44] However, this study was not large enough to reach a definitive conclusion that the boosted f-APV is clinically equivalent to that of the boosted lopinavir. Once-daily administration of ritonavir-boosted f-APV in PI-experienced patients results in poorer virological response than the twice-daily regimen hence it is not recommended to use the once daily ritonavir-boosted f-APV in this group of patients. APV-associated resistance has been detected among patients treated with f-APV[45] but at least 2-3 mutations are required to produce a 10-fold decrease in HIV susceptibility. Data also demonstrated that RTV boosted regimen decrease the likelihood of the development of resistance. In addition, varying degrees of cross-resistance among PIs have been observed.[39]
F-APV is generally well tolerated and can be administered without regard to food.[39] Common side effects include gastrointestinal symptoms, perioral paresthesia, headache and rash.[39] Life-threatening skin reactions have occurred with the use of APV in less than 1% of the patients.[39] Major drug-drug interactions are expected because the drug is extensively metabolized by cytochrome P450 enzymes. Because f-APV contains a sulfonamide moiety, caution should be made in patients with history of sulfonamide allergy.[39] F-APV is metabolized mainly by liver therefore a dose adjustment is needed in patients with hepatic impairment.[39] As with other PIs, lipid abnormalities and abnormal glucose metabolism may occur with the use of the agent.[39] In children, f-APV is approved for use only in adolescents older than 18 years of age. Pharmacokinetics of f-APV in children and the use of its oral suspension in small children are being studied.
Enfuvirtide (T-20; Fuzeon)
Enfuvirtide (T-20) is the first agent of the newest antiretroviral class, fusion inhibitor.[45] It has been approved for treatment of HIV infection in adults and children older than 6 years of age since March 2003. Enfuvirtide is a synthetic peptide that binds to the first heptad-repeat (HR-1)[45] in the gp41 subunit of the viral envelop glycoprotein; this interferes with the formation of a hairpin structure required for fusion of viral and human cellular membranes.[46] Enfuvirtide has an in-vitro antiviral effect against laboratory and clinical isolates of HIV-1 but no activity against HIV-2.[45] Additive and synergistic effects are observed when it is combined with various classes of antiretroviral agents.[46] The approval of enfuvirtide was based on 2 major randomized clinical trials among ART-experienced adult patients[47],[48] receiving either enfuvirtide in combination with a background optimized antiretroviral regimen or a background optimized regimen alone. The optimized antiretroviral background regimen consisted of 3-5 agents selected based on treatment history, tolerance and genotypic and phenotypic resistance profiles. At 48 weeks of treatment, the proportions of patients with viral load less than 400 copies/ml in the enfuvirtide group versus the control group were 34% and 13% respectively, and the proportion with viral load less than 50 copies/ml were 23% and 8%, respectively.[45] In addition, the studies demonstrated that patients with an initial CD4 cell count of more than 100 cells/mm 3, patients with prior exposures to less than 10 antiretroviral agents and patients who had at least 2 active drugs based on the resistance profiles in their optimized regimen are more likely to achieve a plasma viral load level of less than 400 copies/ml.[46] In pediatric population, a study in ART-experienced patients aged 4-12 years demonstrated that 36% of patients had > 1 log 10 decline in HIV-1 RNA and 21% had HIV-1 RNA of less than 400copies/ml at 96 weeks after receiving enfuvirtide-containing regimen.[49] Further studies on safety and efficacy of enfuvirtide in pediatric population are ongoing. Currently, enfuvirtide is recommended for use in combination with other antiretroviral agents in treatment-experienced adults and children older than 6 years of age with evidence of HIV-1 replication despite ongoing antiretroviral therapy.
After subcutaneous injection, 84% of enfuvirtide was absorbed.[45] Ninety percent of the agent was bounded to plasma proteins predominantly albumin.[45] Enfuvirtide undergoes catabolism to its constituent amino acids which are subsequently recycled in the body pool.[45] Clearance of enfuvirtide generally is not affected in patients with renal and liver impairment; however a formal pharmacokinetic study in these populations has not been conducted.[45] Enfuvirtide is not metabolized by cytochrome P450 enzymes hence there is no drug-drug interaction expected when it is co-administered with agents that are metabolized by the cytochrome P450 enzyme system.[45] HIV-1 isolates with reduced susceptibility to enfuvirtide have been observed in vitro[50] in enfuvirtide-naοve heavily ARV-pretreated patients[51] and in patients failing an enfuvirtide-containing regimen.[52] There is no cross resistance between enfuvirtide and other antiretroviral agents.[63] To date, there is no clear evidence from clinical data that virologic outcome of the treatment with enfuvirtide can be predicted by genotypic or phenotypic analysis of the viruses present in patients at treatment initiation.[54]
The most common side effect observed during clinical trials was an injection-site reaction (ISR) which was found in 98% of the patients receiving enfuvirtide.[55] Injection-site reactions that lead to drug discontinuation occurred only in 2% of the patients.[55] Most reactions were mild to moderate in degree, and generally occurred during the first week of enfuvirtide treatment. Common signs and symptoms of ISR include pain or discomfort, indurations, erythema and nodules or cysts.[45] Due to the high incidence of ISR, it is recommended to rotate injection sites to minimize the reaction.[45] Massaging over the area after drug administration may help prevent ISR.[53] Pathophysiology of the ISR is believed to be related to an inflammatory response consistent with localized hypersensitivity as suggested by the biopsy results at an injection site.[56] An increased incidence of pneumonia was also observed among patient receiving enfuvirtide.[47], [58] The relation between pneumonia and the use of enfuvirtide is unclear.[47], [48] Patients should be monitored closely during treatment especially those with risk factors for pneumonia which are low initial CD4 cell counts, high initial viral loads, intravenous drug use, smoking and a prior history of lung diseases.[45] Hypersensitivity reaction occurred in less than 1% of the patients and it is not recommended to restart the agent in those with symptoms and signs consistent with systemic hypersensitivity reactions.[45] Other frequently observed adverse reactions were diarrhea, nausea and fatigue.[45] In pediatric population, adverse reactions from enfuvirtide are similar to those in adults.[45]
Enfuvirtide is to be administered by subcutaneous injection. The recommended dose for adolescent and adults is 90 mg twice a day. For children 6 to 16 years of age, the recommended dose is 2 mg/kg per dose twice daily with the maximum of 90 mg per dose.[45] Patients should be informed about ISR, the risk of pneumonia and the possibility of systemic hypersensitivity reaction. Injection instruction must be followed appropriately.
Tipranavir (TPV; Aptivus)
Tipranavir ( TPV ) is the latest antiretroviral agent that had been approved for the treatment of HIV infection. It is a non-peptidic protease inhibitor which differs from currently available protease inhibitors which belong to the peptidomimetic group.[57] The non-peptidic structure of TPV allows the drug to bind and fit into the active pocket of the protease enzyme of the PI-resistant viruses resulting in the robust activity against PI-resistant HIV strains.[58] In in vitro studies, TPV demonstrated an antiviral activity against a broad panel of HIV-1 including those that have developed resistance to other PIs.[58] TPV has as additive effect when it is combined with NNRTIs and NRTIs.[59] Synergistic activity is observed with the fusion inhibitor, enfuvirtide. When co-administered with RTV, additive and synergistic effect were demonstrated[60] and both median minimum concentration and maximum concentration of TPV were substantially increased.[61] From the aforementioned pharmacokinetic profiles, in order to achieve effective TPV plasma concentration using a twice-daily dosing regimen, co-administration with RTV is essential.[59] As many as 16-20 mutations in the protease gene are needed for HIV to become resistant to TPV whereas only few mutations are needed to develop resistance to the peptidomimetic PIs.[57] TPV has sustained an antiviral activity against isolates with high levels of resistance to PIs such as nelfinavir, ritonavir and indinavir.[62] TPV-resistant viruses also show cross resistance to other peptidomimetic PIs but will remain sensitive to saquinavir.[59]
The approval of TPV was based on the data from two clinical trials in antiretroviral-experienced adult.[63],[64] The patients in the studies had used all three classes of antiretroviral drugs, had failed a PI-based regimen, had viral loads of more than 1000 copies/ml, and had at least one primary protease gene mutation. Ritonavir-boosted TPV or a ritonavir-boosted PI was given in combination with an optimized background regimen based on the genotypic resistance assay. Through 24 weeks of treatment, pooled data from the 2 studies demonstrated that the proportions of patients in TPV group and PI group with viral loads less than 400 copies/ml were 34% and 16%, respectively. The proportions in the two treatment group with viral loads less than 50 copies/ml were 23% and 9%, respectively.[59] In addition, a better virologic outcome was observed in patients who received enfuvirtide in combination with TPV regimen.[59]
TPV should be taken with high fat meal or a light snack to enhance its absorption.[59] The drug is metabolized mainly by cytochrome P450 enzymes hence extensive drug-drug interactions may occur.[59] TPV is excreted unchanged mainly in feces.[59] The most frequent side effects are diarrhea, nausea, fatigue, headache and vomiting.[59] TPV when co-administered with RTV has been associated with clinical hepatitis and fatal hepatic decompensation.65 Grade 3 and 4 increases in transaminase enzymes were observed in 6% of healthy volunteers in a phase-I study and in 6% of subjects receiving TPV in a phase-III study.65 The risks for transaminase elevation and hepatic decompensation are higher in those with chronic hepatitis B or hepatitis C co-infection and those with prior transaminase elevation.[59] Liver function tests should be performed before and frequently throughout the duration of treatment with TPV.[59] Similar to other PIs, new onset diabetes and exacerbation of pre-existing diabetes have been reported.[59] TPV contains a sulfonamide moiety therefore caution should be made in patients with sulfonamide allergy.65 Mild to moderate rashes has been observed with the use of TPV.[59] Triglyceride and cholesterol testing should be performed periodically because TPV increases triglyceride and cholesterol levels.[59]
The recommended dose for TPV is 500 mg in combination with RTV 200 mg per dose twice daily.[59] Treatment history and genotypic or phenotypic resistance assays should be performed to guide the optimized use of TPV since the number of PI mutations affect the virologic response to the agent.[59] Safety and effectiveness in pediatric population as well as the risk-benefit of TPV in ART-naοve adult patients have not been established.65 Phase-III trials in adults with multi-drug resistance HIV are ongoing.
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29. Murphy RL, Sanne I, Cahn P, Phanuphak P, Percival L, Kelleher T et al. Dose-ranging, randomized, clinical trial of atazanavir with lamivudine and stavudine in antiretroviral-naive subjects: 48-week results. Aids 2003; 17(18) : 2603-2614.
30. Squires K, Lazzarin A, Gatell JM, Powderly WG, Pokrovskiy V, Delfraissy JF et al. Comparison of once-daily atazanavir with efavirenz, each in combination with fixed-dose zidovudine and lamivudine, as initial therapy for patients infected with HIV. J Acquir Immune Defic Syndr 2004; 36(5) : 1011-1019.
31. Nieto-Cisneros L, Zala C, Fessel EJ, Gonzalez-Garcia J, Cohen C, McGovern R et al. Antiviral efficacy, metabolic changes and safety of atazanavir ( atv0 ) versus lopinavir/ritonavir ( lpv/rtv0 ) in combination with two nrtis in patients who have experienced virological failure with prior pi-containing regimen(s): 24-week results from BMS AI424-043. In 2nd International AIDS Society Conference on HIV Pathogenesis and Treatment ; 2003; Paris, France: Antiviral Therapy 2003; 8(Suppl. 1):S212; 2003.
32. Johnson M, Grinsztejn B, Rodriguez C, Coco J, DeJesus E, Lazzarin A et al. Atazanavir plus ritonavir or saquinavir, and lopinavir/ritonavir in patients experiencing multiple virological failures. Aids 2005; 19(7) : 685-694.
33. Schnell T, Schmidt B, Moschik G, Thein C, Paatz C, Korn K et al. Distinct cross-resistance profiles of the new protease inhibitors amprenavir, lopinavir, and atazanavir in a panel of clinical samples. Aids 2003; 17(8) : 1258-1261.
34. Musial BL, Chojnacki JK, Coleman CI. Atazanavir: a new protease inhibitor to treat HIV infection. Am J Health Syst Pharm 2004; 61(13) : 1365-1374.
35. Sanne I, Piliero P, Squires K, Thiry A, Schnittman S. Results of a phase 2 clinical trial at 48 weeks (AI424-007): a dose-ranging, safety, and efficacy comparative trial of atazanavir at three doses in combination with didanosine and stavudine in antiretroviral-naive subjects. J Acquir Immune Defic Syndr 2003; 32(1) : 18-29.
36. Haas DW, Zala C, Schrader S, Piliero P, Jaeger H, Nunes D et al. Therapy with atazanavir plus saquinavir in patients failing highly active antiretroviral therapy: a randomized comparative pilot trial. Aids 2003; 17(9) : 1339-1349.
37. Mobius U, Lubach-Ruitman M, Castro-Frenzel B, Stoll M, Esser S, Voigt E et al. Switching to atazanavir improves metabolic disorders in antiretroviral-experienced patients with severe hyperlipidemia. J Acquir Immune Defic Syndr 2005; 39(2) : 174-180.
38. Haerter G, Manfras BJ, Mueller M, Kern P, Trein A. Regression of lipodystrophy in HIV-infected patients under therapy with the new protease inhibitor atazanavir. Aids 2004;18(6):952-955.
39. Lexiva package insert. Available from URL:http://www.hivandhepatitis.com//recent/protease/Lexiva%2010-20-03%20Clean.pdf Accessed 1st September 2005.
40. Falcoz C, Jenkins JM, Bye C, Hardman TC, Kenney KB, Studenberg S et al. Pharmacokinetics of GW433908, a prodrug of amprenavir, in healthy male volunteers. J Clin Pharmacol 2002; 42(8) : 887-898.
41. Wood R, Arasteh K, Stellbrink HJ, Teofilo E, Raffi F, Pollard RB et al. Six-week randomized controlled trial to compare the tolerabilities, pharmacokinetics, and antiviral activities of GW433908 and amprenavir in human immunodeficiency virus type 1-infected patients. Antimicrob Agents Chemother 2004; 48(1) : 116-123.
42. Gathe JC, Jr., Ive P, Wood R, Schurmann D, Bellos NC, DeJesus E et al. SOLO: 48-week efficacy and safety comparison of once-daily fosamprenavir /ritonavir versus twice-daily nelfinavir in naive HIV-1-infected patients. Aids 2004;18(11):1529-1537.
43. Rodriguez-French A, Boghossian J, Gray GE, Nadler JP, Quinones AR, Sepulveda GE et al. The NEAT study: a 48-week open-label study to compare the antiviral efficacy and safety of GW433908 versus nelfinavir in antiretroviral therapy-naive HIV-1-infected patients. J Acquir Immune Defic Syndr 2004; 35(1) : 22-32.
44. Elston RC, Yates P, Tisdale M, Richards N, Whites S, DeJesus E. GW433908 (908)/ritronavir (r): 48 week results in PI-experienced subjects: A retrospective analysis of virological response based on baseline genotype and phenotype. xv International AIDS Conference, July 11-16, 2004; Bangkok, Thailand. http://www.iasociety.org/ejias/print.asp
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45. Roche Laboratories Inc. and Trimeris Inc. Fuzeon package insert. Available from URL:http://www.fuzeon.com/common/fpi.pdf Accessed 1st September 2005.
46. Jamjian MC, McNicholl IR. Enfuvirtide: first fusion inhibitor for treatment of HIV infection. Am J Health Syst Pharm 2004; 61(12) : 1242-1247.
47. Lalezari JP, Henry K, O'Hearn M, Montaner JS, Piliero PJ, Trottier B et al. Enfuvirtide, an HIV-1 fusion inhibitor, for drug-resistant HIV infection in North and South America. N Engl J Med 2003; 348(22) : 2175-2185.
48. Lazzarin A, Clotet B, Cooper D, Reynes J, Arasteh K, Nelson M et al. Efficacy of enfuvirtide in patients infected with drug-resistant HIV-1 in Europe and Australia. N Engl J Med 2003; 348(22) : 2186-2195.
49. Church JA, Hughes M, Chen J, Palumbo P, Mofenson LM, Delora P et al. Long term tolerability and safety of enfuvirtide for human immunodeficiency virus 1-infected children. Pediatr Infect Dis J 2004; 23(8) : 713-718.
50. Reeves JD, Gallo SA, Ahmad N, Miamidian JL, Harvey PE, Sharron M et al. Sensitivity of HIV-1 to entry inhibitors correlates with envelope/coreceptor affinity, receptor density, and fusion kinetics. Proc Natl Acad Sci U S A 2002;99(25):16249-16254.
51. Carmona R, Perez-Alvarez L, Munoz M, Casado G, Delgado E, Sierra M et al. Natural resistance-associated mutations to Enfuvirtide (T20) and polymorphisms in the gp41 region of different HIV-1 genetic forms from T20 naive patients. J Clin Virol 2005; 32(3) : 248-253.
52. Poveda E, Rodes B, Labernardiere JL, Benito JM, Toro C, Gonzalez-Lahoz J et al. Evolution of genotypic and phenotypic resistance to Enfuvirtide in HIV-infected patients experiencing prolonged virologic failure. J Med Virol 2004; 74(1) : 21-28.
53. Moyle G. Stopping HIV fusion with enfuvirtide: the first step to extracellular HAART. J Antimicrob Chemother 2003; 51(2) : 213-217.
54. Miller MD, Hazuda DJ. HIV resistance to the fusion inhibitor enfuvirtide: mechanisms and clinical implications. Drug Resist Updat 2004; 7(2) : 89-95.
55. Kilby JM, Lalezari JP, Eron JJ, Carlson M, Cohen C, Arduino RC et al. The safety, plasma pharmacokinetics, and antiviral activity of subcutaneous enfuvirtide (T-20), a peptide inhibitor of gp41-mediated virus fusion, in HIV-infected adults. AIDS Res Hum Retroviruses 2002; 18(10) : 685-693.
56. Ball RA, Kinchelow T. Injection site reactions with the HIV-1 fusion inhibitor enfuvirtide. J Am Acad Dermatol 2003; 49(5) : 826-831.
57. Plosker GL, Figgitt DP. Tipranavir. Drugs 2003;63(15):1611-1618.
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59. Aptivus package insert.http://www.fda.gov/cder/foi/label/2005/021814lbl.pdf Accessed 1st September 2005.
60. Chong KT, Pagano PJ. In vitro combination of PNU-140690, a human immunodeficiency virus type 1 protease inhibitor, with ritonavir against ritonavir-sensitive and -resistant clinical isolates. Antimicrob Agents Chemother 1997;41(11):2367-2373.
61. Mehandru S, Markowitz M. Tipranavir: a novel non-peptidic protease inhibitor for the treatment of HIV infection. Expert Opin Investig Drugs 2003;12(11):1821-1828.
62. Rusconi S, La Seta Catamancio S, Citterio P, Kurtagic S, Violin M, Balotta C et al. Susceptibility to PNU-140690 (Tipranavir) of human immunodeficiency virus type 1 isolates derived from patients with multidrug resistance to other protease inhibitors. Antimicrob Agents Chemother 2000;44(5):1328-1332.
63. Cooper D, C' H, Cahn P, Lazzarin A, Walmsley S, Arasteh K, et al. 24-week RESIST study analyses: the efficacy of tipranavir/ritronavir (TPV/r) is superior to lopinavir/retronavir (LPV/r), and the TPV/r treatment response is enhanced by inclusion of genotypically active antiretrovirals in the optimized background regimen (OBR) [
Abstract no.560]. 12th Conference on Retroviruses and Opportunistic Infections, Feb 22-25, 2005; Boston. http://medadvocates.org/resources/conferences/croi/12_croi/tipranavir_%20RESIST.pdf Accessed 1st September 2005.
64. Hicks C and the RESIST-1 study team. RESIST-1: A phase 3, randomized, controlled, open-label, multicenter trial comparing tipranavir/ritronavir (TPV/r) to an optimized comparator protease inhibitor/r (CPI/r) regimen in antiretroviral (ARV) experienced patients: 24-week data [
Abstract no.3726]. 44th ICAAC, Oct 31-Nov 2, 2004; Washington, DC. http://medadvocates.org/resources/conferences/icaac/44_icaac/tip_resist.htm Accessed 1st September 2005.(Chearskul Pimpanada, Rong)
Abstract
The advent of combination antiretroviral therapy for the treatment of human immunodeficiency virus (HIV) infection has dramatically changed the prognosis and quality of life of HIV-infected adults and children. To date, there are 21 antiretroviral agents available with only 11 agents being approved for the use in young children less than 6 years of age. The currently available antiretroviral agents belong to four different classes; nucleoside/nucleotide reverse transcriptase inhibitors (NRTI, NtRTI), non-nucleoside reverse transcriptase inhibitors (NNRTI), protease inhibitors (PI), and a new class of fusion inhibitors (FI). It is recommended that the treatment regimen should be a combination of at least 3 drugs from different drug classes as this has been shown to slow disease progression, improve survival, and result in better virologic and immunologic responses. Treatment with antiretroviral agents is frequently complicated by the issues of adherence, tolerability, long term toxicity and drug resistance. Many efforts have been made to develop new antiretroviral agents with greater potency, higher tolerability profiles and better convenience. Some new agents are also effective against drug-resistant strains of HIV. Since 2001, there were 7 new antiretroviral agents and 2 fixed-dose multidrug formulations being approved for the treatment of HIV infection, most are approved only for use in adults. In this article, we will review new antiretroviral agents including emtricitabine, tenofovir disoproxil fumarate, atazanavir, fosamprenavir, tipranavir and enfuvirtide. Pediatric information on these drugs will be provided when available.
Keywords: Antiretroviral drugs; HIV; Children
Emtricitabine (FTC; Emtriva)
Emtricitabine is an NRTI that is structurally similar to lamivudine (3TC), differing only by the addition of a fluorine.[1] When compared to lamivudine, emtricitabine has advantages in term of its longer half life, higher oral bioavailability and greater in vitro activity against HIV.[2], [3] For the treatment in adults, emtricitabine is a component of a preferred initial combination regimen and can be used in place of lamivudine as part of dual NRTI backbone in combination with PI or NNRTI.[4] In clinical trials in HIV-infected adults, emtricitabine-containing combination regimens including the completely once daily regimens, were effective in achieving and /or maintaining suppression of plasma HIV loads to the undetectable levels in both antiretroviral therapy (ART)-naοve[5], [6] and ART-experienced patients switching from a stable combination regimen.[7], [8] When comparing emtricitabine once-daily with stavudine (dAT) twice-daily each in combination with once-daily didanosine and efavirenz in ART-naοve patients, the proportions of patients achieved and maintained HIV RNA <400 copies/ml through week 48 were 81% in FTC group and 68% in d4T group.[5] In ART-experienced patients on lamivudine-containing regimen with HIV RNA <400 copies/ml, 77% of those who were switched from lamivudine to emtricitabine achieved HIV RNA <400 copies/ml at week 48 compare to 82% of those who continued the same regimen.[7] The effectiveness of emtricitabine as a part of combination regimens remains evidenced after 3 - 4 years of treatment.[7] Emtricitabine is also active against hepatitis B virus (HBV)[9] but it has not been approved by Food and Drug Administration (FDA) for use in this indication yet.[10] In children, it is only approved for use in adolescents older than 18 yrs of age.[11] Clinical trials are underway in children using the investigational dose of 6 mg per kg of body weight once daily.[12]
Due to its unique pharmacokinetic characteristics, emtricitabine can be given once daily[13] and without regard to food.[10] Potential drug interaction is minimal because it neither inhibits nor is metabolized by the cytochrome P450 enzyme system.[10] Emtricitabine is excreted by kidney hence dose adjustment is required in patients with renal insufficiency.[10] Tolerability profiles of emtricitabine are similar to those of lamivudine with only minimal toxicities. Common but mild side effects include headache, insomnia, diarrhea, nausea, vomiting and rash.[5], [7] Skin discoloration and hyperpigmentation of palms and soles has been observed in patients using this medication especially in non-Caucasian population.[10] Lactic acidosis, severe hepatomegaly and steatosis occur rarely but can be fatal.[10] Due to its antiviral activity against HBV, there have been cases of HBV exacerbation after discontinuation of emtricitabine[3] therefore screening for HBV/HIV co-infection is recommended before starting treatment with emtricitabine.[4] Liver functions should also be monitored closely for several months after its discontinuation.[4] Resistant profiles of emtricitabine are similar to those of lamivudine and co-administration of the two medications is not recommended.[4] Currently there is a co-formulated product of emtricitabine and tenofovir disoproxil fumarate[14], a new nucleotide analogue reverse transcriptase inhibitor (NtRTI), that can be given once daily in HIV-infected adult patients. The use of this co-formulated product in children is still under study.
Tenofovir Disoproxil Fumarate (Tenofovir DF, TDF; Viread)
Tenofovir disoproxil fumarate is an ester prodrug of tenofovir, an NtRTI.[15] It has been approved for use in combination with other antiretroviral agents for the treatment of HIV infection in adult since October 2001. In pediatric population, it was approved for use only for adolescents older than 18 years of age and is currently under study in children. In in vitro studies, TDF demonstrated a good inhibitory activity against HIV[16] as well as a synergistic/additive effect when combined with other antiretroviral agents.[17] According to the treatment guidelines for HIV-infected adults, TDF is a part of a preferred initial regimen for ART-naοve patients. In a clinical study among ART-naοve adult patients, TDF-containing regimen and the stavudine-containing regimen when each was combined with lamivudine and efavirenz demonstrated virologic suppression with HIV RNA < 400 copies/ml at week 48 in 80% and 84% in TDF group and d4T group, respectively.[18] In ART-experienced adult patients, the data from clinical trials shows that TDF in combination with other antiretroviral agents produced significantly higher viral load reduction than placebo with 40% cases achieved HIV RNA < 400 copies/ml at week 24 in tenofovir group versus 11% in placebo group.[19] In the placebo crossover phase of the study, the proportions of cases with HIV RNA < 400 copies/ml were 28% in TDF group and 30% in those who were switched from placebo to TDF.[19] Because of its once daily dosing, TDF can be used to simplify the treatment regimen among virologically stable patients on a combination antiretroviral therapy.[20] The effectiveness of TDF as a salvage regimen in the case of virologic failure as well as an alternative agent in the case of drug toxicity has also been demonstrated in ART-experienced adult patients.[15] However, suboptimal response and /or early treatment failure have been demonstrated among treatment-naοve patients who received TDF in combination with 3TC and didanosine or 3TC and abacavir.[15]
Due to its long half life of 17 hours, TDF is allowed to be used as a convenient once-daily dosing.[27] Twenty five percent of the drug is absorbed in fasting state and up to 39% is absorbed when given with high fat meal.[21] TDF can be given without regard to food but it is recommended to be taken with high fat meal to enhance its absorption. TDF is eliminated unchanged by kidneys and dose adjustment is required when use in patients with renal insufficiency.[21] Common side effects are that of gastrointestinal disturbances such as nausea, diarrhea, vomiting and flatulence.[21] Severe hepatomegaly with steatosis is the rare but fatal reaction.[22] Although there has been no TDF-associated renal toxicity among adult patients who received TDF up to one year in clinical studies, cases of nephrotoxicity secondary to TDF have been reported in adults.[23],[24] TDF appears less likely to cause mitochondrial toxicity when compared to other NRTIs, however lactic acidosis has been reported with the use of the agent.[24] Similar to 3TC and FTC, TDF has an antiviral activity against HBV[25], therefore exacerbation of HBV after discontinuation of TDF is possible and patients should be screened for HBV prior to initiation of TDF. TDF substantially increases plasma didanosine levels, thus the dosage of didanosine should be decreased to avoid potential toxicity from didanosine. Because TDF lowers plasma atazanavir levels by 25%, a low-dose ritronavir for pharmacokinetic enhancement should always be used in a treatment regimen that contains atazanavir and TDF. In general, resistance to TDF develops slowly and reduced responses to TDF are associated with the L210W, M41L or K65R mutations.
The data is insufficient to make recommendations for the use of TDF in children. With the advantages of convenient once daily dosing without regard to food, less mitochondrial toxicity, fewer drug interaction and slower rate for resistance, TDF is among one of antiretroviral agents with great utility. One of the concerns for use of TDF in children is its potential bone toxicity. There were some evidences of osteomalacia among juvenile animals exposed to high dose TDF.[26] Clinical trials in children are underway.
Atazanavir (ATV; Reyataz)
Atazanavir ( ATV ) is an azapeptide HIV-1 protease inhibitor that targets the protease enzyme, ultimately preventing formation of mature virions.[27] In in-vitro studies, ATV had demonstrated antiviral activity against HIV 2- to 20-fold more potent than other available PIs.[28] ATV is a part of an alternative PI-based combination regimen for the treatment of ART-naοve patients according to the treatment guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. In a clinical trial among antiretroviral naοve adult, the efficacy of ATV was comparable to that of nelfinavir (NFV) with 67% in ATV group and 59% in nelfinavir group achieved HIV RNA of less than 400 copies/ml at week 48, and to that of efavirenz with 67% in ATV group and 62% in efavirenz group achieved HIV RNA of less than 400 copies/ml at week 48 when each was combined with two NRTIs.[29], [30] In ART-experienced patients, the effectiveness of ATV was in the lesser extent compared to lopinavir-ritronavir with the proportions of cases achiving HIV RNA < 400 copies/ml were 49% in ATV group and 69% in LPV group when each drug was combined with 2 NRTIs.[31] In a study in ART-experienced patients who had failed at least 2 regimens, atazanavir-ritonavir and lopinavir-ritonavir each in combination with TDF and 1 NRTI demonstrated a comparable antiretroviral activity with 55% and 57% cases achieved HIV RNA < 400 copies/ml at week 48 in ATV group and LPV group respectively, and both regimens were superior to atazanavir-saquinavir-containing regimen.[32] The concern for use of ATV in ART-experienced patients is the resistance issue. In one study in patients who have previously taken PI, 40% had a reduced susceptibility to ATV.[33] A low dose ritonavir to enhance the pharmacokinetics of ATV should be administered in PI-experienced patients starting on an ATV-containing regimen.
Administration of ATV with a light meal increases its absorption.[27] Antacid, H 2 -blocker or proton pump inhibitor interfere with drug absorption.[24],[34] When used with didanosine, ATV should be taken at least 2 hours before or 1 hour after didanosine to avoid the interference.[27] ATV can be given once daily due to its half-life of 7 hours.[27] It is metabolized mainly by cytochrome P-450 pathway.[27] It is both an inhibitor and a substrate of the enzyme, therefore major drug-drug interaction is expected.[27] Dose adjustment should also be made when used in patients with hepatic insufficiency.[27] One of the advantages of ATV is the lower pill burden with only two pills per day; this may result in better adherence to treatment. Adverse reactions from ATV are generally comparable to those described in protease inhibitors.[35] Common side effects include jaundice, headache, rash and nausea.[34] Hyperbillirubinemia with or without jaundice has been reported during clinical trials of ATV in 35%-49% of patients.[34] The elevations of billirubin commonly occur within the first week of treatment; it is dose-related, reversible after drug discontinuation and not associated with elevation of transaminase enzymes.[34] Prolonged PR interval and asymptomatic first degree AV block are among cardiac effects that have been observed in healthy volunteers receiving ATV.[27] The drug should be used with caution in patients with conduction defect or patients receiving concomitant medications that have the same cardiac side effects.[27] Rare but potential life threatening side effect including Steven Johnson syndrome and severe hepatotoxicity may occur.[33] Hyperglycemia and exacerbation of diabetes mellitus may occur with the use of ATV.[27] Regarding the incidence of lipodystrophy which is one of the major concerns associated with the use of PI, ATV does not disrupt lipids to the same extent as other PIs.[30], [35], [36] In one study, ATV had the same lipid effects as EFV.[30] When ART-experienced patients with severe hyperlipidemia change their treatment regimen to ATV, a sustained improvement in lipid profiles was observed while virologic control was still maintained.[37], [38]
For the use of ATV in children, currently there are insufficient data to make any recommendation. ATV is not approved for use in children less than 16 years of age. The drug should not be used in infants less than 3 months-old due to the possibility of kernicterus. In children, larger dose than adults may be needed and dose finding studies are ongoing. The dose of ATV for adolescents older than 16 years of age is 400 mg once daily in ART-naοve patients and 300 mg in combination with 100 mg of ritonavir once daily in ART-experienced patients. When co-administered with efavirenz or TDF, ATV should always be boosted with ritonavir. In summary, the advantages of ATV are the convenience of once daily dosing, less pill burden and its minimal effect on lipid profiles compares to other PIs.
Fosamprenavir (f-APV, FPV; Lexiva)
Fosamprenavir (f-APV) is a prodrug of an HIV protease inhibitor, amprenavir (APV).[39] It has been approved for use in combination with other ARV agents for the treatment of HIV infection in adults since October 2003. After oral administration, f-APV is rapidly hydrolyzed to amprenavir, the active substrate, by enzymes in the gut epitheliums as it is absorbed.[39] The prodrug formulation of f-APV, with improved solubility[40], substantially reduces the number of tablets per dose when compared to the parent molecule APV.[41] From the pharmacokinetic study in healthy adult volunteers, f-APV delivers plasma concentrations equivalent to the recommended therapeutic dose of APV but with less pill burden.[40] Fosamprenavir also demonstrated less gastrointestinal side effects when compared to APV.[41] In two clinical trials in ART-naοve adult patients, f-APV and ritonavir boosted f-APV demonstrated the similar virological and immunological efficacy as nelfinavir when each was combined with abacavir and 3TC.[42], [43] In ART-experienced patients with prior virological failure, 58% of patients who received a ritonavir-boosted f-APV regimen achieved and maintained virologic suppression with HIV RNA of less than 400 copies/ml at week 48 compared to 61% of those who received a ritonavir-boosted lopinavir regimen.[44] However, this study was not large enough to reach a definitive conclusion that the boosted f-APV is clinically equivalent to that of the boosted lopinavir. Once-daily administration of ritonavir-boosted f-APV in PI-experienced patients results in poorer virological response than the twice-daily regimen hence it is not recommended to use the once daily ritonavir-boosted f-APV in this group of patients. APV-associated resistance has been detected among patients treated with f-APV[45] but at least 2-3 mutations are required to produce a 10-fold decrease in HIV susceptibility. Data also demonstrated that RTV boosted regimen decrease the likelihood of the development of resistance. In addition, varying degrees of cross-resistance among PIs have been observed.[39]
F-APV is generally well tolerated and can be administered without regard to food.[39] Common side effects include gastrointestinal symptoms, perioral paresthesia, headache and rash.[39] Life-threatening skin reactions have occurred with the use of APV in less than 1% of the patients.[39] Major drug-drug interactions are expected because the drug is extensively metabolized by cytochrome P450 enzymes. Because f-APV contains a sulfonamide moiety, caution should be made in patients with history of sulfonamide allergy.[39] F-APV is metabolized mainly by liver therefore a dose adjustment is needed in patients with hepatic impairment.[39] As with other PIs, lipid abnormalities and abnormal glucose metabolism may occur with the use of the agent.[39] In children, f-APV is approved for use only in adolescents older than 18 years of age. Pharmacokinetics of f-APV in children and the use of its oral suspension in small children are being studied.
Enfuvirtide (T-20; Fuzeon)
Enfuvirtide (T-20) is the first agent of the newest antiretroviral class, fusion inhibitor.[45] It has been approved for treatment of HIV infection in adults and children older than 6 years of age since March 2003. Enfuvirtide is a synthetic peptide that binds to the first heptad-repeat (HR-1)[45] in the gp41 subunit of the viral envelop glycoprotein; this interferes with the formation of a hairpin structure required for fusion of viral and human cellular membranes.[46] Enfuvirtide has an in-vitro antiviral effect against laboratory and clinical isolates of HIV-1 but no activity against HIV-2.[45] Additive and synergistic effects are observed when it is combined with various classes of antiretroviral agents.[46] The approval of enfuvirtide was based on 2 major randomized clinical trials among ART-experienced adult patients[47],[48] receiving either enfuvirtide in combination with a background optimized antiretroviral regimen or a background optimized regimen alone. The optimized antiretroviral background regimen consisted of 3-5 agents selected based on treatment history, tolerance and genotypic and phenotypic resistance profiles. At 48 weeks of treatment, the proportions of patients with viral load less than 400 copies/ml in the enfuvirtide group versus the control group were 34% and 13% respectively, and the proportion with viral load less than 50 copies/ml were 23% and 8%, respectively.[45] In addition, the studies demonstrated that patients with an initial CD4 cell count of more than 100 cells/mm 3, patients with prior exposures to less than 10 antiretroviral agents and patients who had at least 2 active drugs based on the resistance profiles in their optimized regimen are more likely to achieve a plasma viral load level of less than 400 copies/ml.[46] In pediatric population, a study in ART-experienced patients aged 4-12 years demonstrated that 36% of patients had > 1 log 10 decline in HIV-1 RNA and 21% had HIV-1 RNA of less than 400copies/ml at 96 weeks after receiving enfuvirtide-containing regimen.[49] Further studies on safety and efficacy of enfuvirtide in pediatric population are ongoing. Currently, enfuvirtide is recommended for use in combination with other antiretroviral agents in treatment-experienced adults and children older than 6 years of age with evidence of HIV-1 replication despite ongoing antiretroviral therapy.
After subcutaneous injection, 84% of enfuvirtide was absorbed.[45] Ninety percent of the agent was bounded to plasma proteins predominantly albumin.[45] Enfuvirtide undergoes catabolism to its constituent amino acids which are subsequently recycled in the body pool.[45] Clearance of enfuvirtide generally is not affected in patients with renal and liver impairment; however a formal pharmacokinetic study in these populations has not been conducted.[45] Enfuvirtide is not metabolized by cytochrome P450 enzymes hence there is no drug-drug interaction expected when it is co-administered with agents that are metabolized by the cytochrome P450 enzyme system.[45] HIV-1 isolates with reduced susceptibility to enfuvirtide have been observed in vitro[50] in enfuvirtide-naοve heavily ARV-pretreated patients[51] and in patients failing an enfuvirtide-containing regimen.[52] There is no cross resistance between enfuvirtide and other antiretroviral agents.[63] To date, there is no clear evidence from clinical data that virologic outcome of the treatment with enfuvirtide can be predicted by genotypic or phenotypic analysis of the viruses present in patients at treatment initiation.[54]
The most common side effect observed during clinical trials was an injection-site reaction (ISR) which was found in 98% of the patients receiving enfuvirtide.[55] Injection-site reactions that lead to drug discontinuation occurred only in 2% of the patients.[55] Most reactions were mild to moderate in degree, and generally occurred during the first week of enfuvirtide treatment. Common signs and symptoms of ISR include pain or discomfort, indurations, erythema and nodules or cysts.[45] Due to the high incidence of ISR, it is recommended to rotate injection sites to minimize the reaction.[45] Massaging over the area after drug administration may help prevent ISR.[53] Pathophysiology of the ISR is believed to be related to an inflammatory response consistent with localized hypersensitivity as suggested by the biopsy results at an injection site.[56] An increased incidence of pneumonia was also observed among patient receiving enfuvirtide.[47], [58] The relation between pneumonia and the use of enfuvirtide is unclear.[47], [48] Patients should be monitored closely during treatment especially those with risk factors for pneumonia which are low initial CD4 cell counts, high initial viral loads, intravenous drug use, smoking and a prior history of lung diseases.[45] Hypersensitivity reaction occurred in less than 1% of the patients and it is not recommended to restart the agent in those with symptoms and signs consistent with systemic hypersensitivity reactions.[45] Other frequently observed adverse reactions were diarrhea, nausea and fatigue.[45] In pediatric population, adverse reactions from enfuvirtide are similar to those in adults.[45]
Enfuvirtide is to be administered by subcutaneous injection. The recommended dose for adolescent and adults is 90 mg twice a day. For children 6 to 16 years of age, the recommended dose is 2 mg/kg per dose twice daily with the maximum of 90 mg per dose.[45] Patients should be informed about ISR, the risk of pneumonia and the possibility of systemic hypersensitivity reaction. Injection instruction must be followed appropriately.
Tipranavir (TPV; Aptivus)
Tipranavir ( TPV ) is the latest antiretroviral agent that had been approved for the treatment of HIV infection. It is a non-peptidic protease inhibitor which differs from currently available protease inhibitors which belong to the peptidomimetic group.[57] The non-peptidic structure of TPV allows the drug to bind and fit into the active pocket of the protease enzyme of the PI-resistant viruses resulting in the robust activity against PI-resistant HIV strains.[58] In in vitro studies, TPV demonstrated an antiviral activity against a broad panel of HIV-1 including those that have developed resistance to other PIs.[58] TPV has as additive effect when it is combined with NNRTIs and NRTIs.[59] Synergistic activity is observed with the fusion inhibitor, enfuvirtide. When co-administered with RTV, additive and synergistic effect were demonstrated[60] and both median minimum concentration and maximum concentration of TPV were substantially increased.[61] From the aforementioned pharmacokinetic profiles, in order to achieve effective TPV plasma concentration using a twice-daily dosing regimen, co-administration with RTV is essential.[59] As many as 16-20 mutations in the protease gene are needed for HIV to become resistant to TPV whereas only few mutations are needed to develop resistance to the peptidomimetic PIs.[57] TPV has sustained an antiviral activity against isolates with high levels of resistance to PIs such as nelfinavir, ritonavir and indinavir.[62] TPV-resistant viruses also show cross resistance to other peptidomimetic PIs but will remain sensitive to saquinavir.[59]
The approval of TPV was based on the data from two clinical trials in antiretroviral-experienced adult.[63],[64] The patients in the studies had used all three classes of antiretroviral drugs, had failed a PI-based regimen, had viral loads of more than 1000 copies/ml, and had at least one primary protease gene mutation. Ritonavir-boosted TPV or a ritonavir-boosted PI was given in combination with an optimized background regimen based on the genotypic resistance assay. Through 24 weeks of treatment, pooled data from the 2 studies demonstrated that the proportions of patients in TPV group and PI group with viral loads less than 400 copies/ml were 34% and 16%, respectively. The proportions in the two treatment group with viral loads less than 50 copies/ml were 23% and 9%, respectively.[59] In addition, a better virologic outcome was observed in patients who received enfuvirtide in combination with TPV regimen.[59]
TPV should be taken with high fat meal or a light snack to enhance its absorption.[59] The drug is metabolized mainly by cytochrome P450 enzymes hence extensive drug-drug interactions may occur.[59] TPV is excreted unchanged mainly in feces.[59] The most frequent side effects are diarrhea, nausea, fatigue, headache and vomiting.[59] TPV when co-administered with RTV has been associated with clinical hepatitis and fatal hepatic decompensation.65 Grade 3 and 4 increases in transaminase enzymes were observed in 6% of healthy volunteers in a phase-I study and in 6% of subjects receiving TPV in a phase-III study.65 The risks for transaminase elevation and hepatic decompensation are higher in those with chronic hepatitis B or hepatitis C co-infection and those with prior transaminase elevation.[59] Liver function tests should be performed before and frequently throughout the duration of treatment with TPV.[59] Similar to other PIs, new onset diabetes and exacerbation of pre-existing diabetes have been reported.[59] TPV contains a sulfonamide moiety therefore caution should be made in patients with sulfonamide allergy.65 Mild to moderate rashes has been observed with the use of TPV.[59] Triglyceride and cholesterol testing should be performed periodically because TPV increases triglyceride and cholesterol levels.[59]
The recommended dose for TPV is 500 mg in combination with RTV 200 mg per dose twice daily.[59] Treatment history and genotypic or phenotypic resistance assays should be performed to guide the optimized use of TPV since the number of PI mutations affect the virologic response to the agent.[59] Safety and effectiveness in pediatric population as well as the risk-benefit of TPV in ART-naοve adult patients have not been established.65 Phase-III trials in adults with multi-drug resistance HIV are ongoing.
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